University of Pittsburgh, Pittsburgh, PA 15213, USA.
J Antimicrob Chemother. 2012 Sep;67(9):2139-42. doi: 10.1093/jac/dks173. Epub 2012 May 11.
Coital use of 1% tenofovir gel was shown to be modestly effective at preventing HIV transmission when applied vaginally in the CAPRISA 004 trial. Because the gel is hyperosmolar, which would reduce the integrity of the epithelium and induce fluid movement into the lumen, rectal use may not be acceptable. This study evaluated the pre-clinical safety and efficacy of a reformulated (reduced osmolality) tenofovir gel product.
Reduced glycerine (RG)-tenofovir gel was compared with the original tenofovir gel for physiochemical characteristics, product safety and anti-HIV-1 activity.
The formulations were similar in all characteristics except for osmolality and spreadability/firmness. The RG-tenofovir gel had a 73% lower osmolality, a 29.6% increase in spreadability and a 27% decrease in firmness as compared with the original tenofovir gel. When applied to epithelial cell monolayers, tenofovir gel showed a transient reduction in the transepithelial resistance while the RG-tenofovir gel did not. Both gels retained ectocervical and colorectal explant viability. However, tenofovir gel treatment resulted in epithelial stripping that was absent after RG-tenofovir gel treatment of the polarized explants. Anti-HIV-1 activity was confirmed by lack of HIV-1 infection in polarized explants treated with either gel as compared with the control explants.
Reducing the osmolality of the tenofovir gel resulted in improved epithelial integrity, which suggests better safety upon rectal use. The improved gel safety did not compromise drug release or anti-HIV-1 activity. These data support the use of this gel as a dual compartment microbicide.
在 CAPRISA 004 试验中，经阴道使用 1%替诺福韦凝胶显示出对预防 HIV 传播具有一定效果。由于该凝胶具有高渗性，会降低上皮完整性并诱导液体流入管腔，因此直肠使用可能不可接受。本研究评估了一种改良（降低渗透压）替诺福韦凝胶产品的临床前安全性和疗效。
比较了改良甘油（RG）-替诺福韦凝胶与原始替诺福韦凝胶的理化特性、产品安全性和抗 HIV-1 活性。
除渗透压和铺展性/硬度外，两种配方在所有特性上均相似。与原始替诺福韦凝胶相比，RG-替诺福韦凝胶的渗透压降低了 73%，铺展性增加了 29.6%，硬度降低了 27%。替诺福韦凝胶用于上皮细胞单层时，跨上皮电阻会短暂降低，而 RG-替诺福韦凝胶则不会。两种凝胶均保留了宫颈和结直肠外植体的活力。然而，替诺福韦凝胶处理会导致上皮剥离，而 RG-替诺福韦凝胶处理极化外植体后则不会出现这种情况。与对照外植体相比，用任一种凝胶处理的极化外植体均未发生 HIV-1 感染，证实了其抗 HIV-1 活性。
降低替诺福韦凝胶的渗透压可改善上皮完整性，提示直肠使用时安全性更好。改善的凝胶安全性并未影响药物释放或抗 HIV-1 活性。这些数据支持将该凝胶用作双腔室杀微生物剂。
